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Sarco(endo)plasmic reticulum Ca2+ ATPase isoforms and their role in muscle physiology and pathology
1Laboratory of Molecular Cardiology, University of Cincinnati College of Medicine, Ohio 45267, USA.
Abstract:
Recent studies suggest that SR Ca2+ transport function is altered in hypertrophied and failing myocardium. To understand whether alterations in SR Ca2+ ATPase levels affect myocardial contractility, we generated transgenic mice that specifically overexpress SERCA2a or SERCA1 pump in the mouse heart, using the cardiac alpha-MHC promoter. Analysis of SERCA2a transgenic mice show both an increase in mRNA and protein levels (120-150% of the wild type). Isolated work performing heart preparations revealed that SERCA2a mice have improved myocardial performance. On the other hand, SERCA1 overexpression in the heart resulted in isoform replacement without any change in total SERCA protein. Interestingly, SERCA1 transgenic hearts exhibited super contractility with a significant increase in rates of muscle contraction (+dp/dt) and relaxation (-dp/dT). The time to peak pressure and half-time to relaxation were significantly shorter.
Insights
Altering sarcoplasmic reticulum calcium transport by overexpressing SERCA2a improved heart function in mice. Overexpressing SERCA1, however, led to super contractility, enhancing muscle contraction and relaxation rates.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cardiac Physiology
Background:
- Sarcoplasmic reticulum (SR) Ca2+ transport is crucial for cardiac function.
- Altered SR Ca2+ handling is implicated in myocardial hypertrophy and heart failure.
- The role of specific SR Ca2+ ATPase (SERCA) isoforms in contractility requires further elucidation.
Purpose of the Study:
- To investigate the impact of SERCA2a and SERCA1 overexpression on myocardial contractility.
- To determine how altered SR Ca2+ ATPase levels affect cardiac performance in transgenic mouse models.
Main Methods:
- Generation of transgenic mice overexpressing SERCA2a or SERCA1 under the cardiac alpha-MHC promoter.
- Quantitative analysis of SERCA mRNA and protein levels.
- Assessment of myocardial performance using isolated working heart preparations.
Main Results:
- SERCA2a transgenic mice exhibited increased SERCA2a mRNA and protein levels (120-150% of wild type).
- SERCA2a overexpression resulted in improved myocardial performance in isolated hearts.
- SERCA1 overexpression led to isoform replacement without altering total SERCA protein levels.
- SERCA1 transgenic hearts displayed enhanced contractility, with significant increases in rates of contraction (+dp/dt) and relaxation (-dp/dT), and shorter relaxation times.
Conclusions:
- SERCA2a overexpression enhances cardiac performance, suggesting a therapeutic potential for heart failure.
- SERCA1 isoform replacement in the heart can lead to super contractility, indicating a distinct functional role.
- These findings highlight the differential effects of SERCA isoforms on myocardial contractility and relaxation dynamics.